NM_000939.4:c.250T>C

Variant names:

• chr2-25161635-A-G
• rs748145117
• NM_000939.4:c.250T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000939.4(POMC):​c.250T>C​(p.Trp84Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,401,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W84G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POMC NM_000939.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.91
• Publications: 6 publications found

Genes affected

POMC (HGNC:9201): (proopiomelanocortin) This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]

POMC Gene-Disease associations (from GenCC):

• obesity due to pro-opiomelanocortin deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• inherited obesity

  Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.250T>C	p.Trp84Arg	missense_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.250T>C	p.Trp84Arg	missense_variant	Exon 4 of 4		NP_001030333.1
POMC	NM_001319204.2	c.250T>C	p.Trp84Arg	missense_variant	Exon 4 of 4		NP_001306133.1
POMC	NM_001319205.2	c.250T>C	p.Trp84Arg	missense_variant	Exon 3 of 3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.250T>C	p.Trp84Arg	missense_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000663 AC: 1 AN: 150928 AF XY: 0.0000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401010 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 691554

African (AFR) AF: 0.00 AC: 0 AN: 31550

American (AMR) AF: 0.00 AC: 0 AN: 35984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35876

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080888

Other (OTH) AF: 0.00 AC: 0 AN: 58034

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000934 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;D;D;D;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	0.97	D;.;.;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.7	M;M;M;M;.
PhyloP100		3.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.9	D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		0.99	D;D;D;D;.
Vest4		0.65
MutPred		0.48		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.99
MPC		1.3
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.55
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs748145117; hg19: chr2-25384504;